益气活血法通过JNK/SAPK信号通路影响海绵体神经损伤后海绵体平滑肌细胞表型转化的机制研究

The treatment of erectile dysfunction (ED) after the operation of the prostate cancer is one of the difficult problems. Even the patients with nerve-sparing radical prostatectomy (RP) is also prone to develop ED, and the effects of the phosphodiesterase type 5 (PDE-5) inhibitor are not satisfied for this ED.Recent studies about the ED after the RP have demonstrated that the male's spontaneous nocturnal erection are destroyed after cavernosal nevers injured, that will cause hypoxia in the cavernous tissue , and lead to damage to the structure of corpora cavernosum smooth muscle cells(CCSMC), and to occur refractory ED for a long time.The phenotypic modulation of CCSMC play a key role in cavernosal fibrosis induced by hypoxia, it is expected to reverse cavernous fibrosis by intervening in the stage of phenotypic modulation. .The data at home and abroad and our previous researcher were demonstrated that JNK/SAPKs signaling pathway is involved in the regulation of CCSMC phenotypic modulation. In our clinic, we found that Salidroside I can effectively improve erectile function in ED patients, and inhibits the CCSMC phenotype modulation in rat, but the exact molecular mechanism underlying these changes remain unclear. This study is to take the neurogenic ED of the cavernous nerve injury as a breakthrough point, and to explore whether the method of Reinforcing Qi and Activating Blood can control the CCSMC phenotypic modulation by regulating the JNK/SAPKs signaling pathway, so as to treat ED. The research is expected to provide new strategies for the diagnosis and treatment of ED, and also provide new ideas for the research and development of traditional Chinese medicine for the treatment of ED.

前列腺癌术后勃起功能障碍（ED）是当前的治疗难题之一，这类患者采用经典的磷酸二酯酶5型(PDE-5)抑制剂疗效不满意。目前研究认为，RP术后ED的发生主要原因是阴茎海绵体平滑肌细胞（CCSMC）发生表型转化，久之则引发海绵体纤维化，故发生难治性ED。国内外的资料和我们前期的研究发现，JNK/SAPKs信号通路参与CCSMC表型转化的调控。我们在临床发现，益气活血的红景I号能有效改善ED患者的勃起功能，动物实验发现其可抑制大鼠海绵体CCSMC表型转化，但机制不明确。因此，本课题拟以海绵体神经损伤的神经性ED为切入点，从体内体外实验探讨中医益气活血补肾法是否可以通过调节JNK/SAPKs信号通路抑制阴茎海绵体SMC表型转化，从而治疗ED。本课题的完成有望为ED的临床治疗提供新策略，同时为开发和研究治疗ED的中药提供新思路。

前列腺癌术后勃起功能障碍（ED）是当前的治疗难题之一，我们在临床发现，益气活血的红景1号能有效改善患者的勃起功能，但机制不明。本课题建立阴茎海绵体平滑肌细胞（CCSMC）缺氧模型及大鼠双侧海绵体神经夹损伤动物模型（CNCI），研究红景1号是否通过MAPK信号通路调控CCSMC表型转化，从而治疗ED。. 细胞实验设常氧组(21％O2)、缺氧组(1％O2)和缺氧+含药血清组。结果提示：与常氧组比较，缺氧组α-SMA、p38、磷酸化p38丝裂原活化蛋白激酶(P-p38 MAPK)蛋白相对表达量明显降低(P<0.05)，缺氧诱导因子-1 a(HIF-1 a)、胶原蛋白I(Collagen I)相对表达量均明显升高(均P<0.05)，而P-JNK、P-ERK蛋白相对表达量差异无统计学意义(P>0.05)。与缺氧组相比，缺氧+含药血清组 a-SMA、Desmin、P38、p-P38的相对表达量均增加，而HIF-1a和Collagen-1表达减少。.动物实验分为对照组（sham组）、CNCI组、药物组（CNCI+红景1号组）。结果提示：CN损伤后第4周ICP显著下降，同时 ICP/MAP比率也明显下降，说明大鼠勃起功能受损。CNCI组与sham组相比，ERK、p-ERK、JNK、p-JNK没有统计学意义，P38及p-p38 变化有统计学差异。相较于CNCI组，药物组a-SMA和p-P38表达上升。. 动物实验和细胞实验初步表明：红景1号是通过P38-MAPK通路抑制大鼠CCSMC的表型转化，从而改善大鼠勃起功能。本课题申请时我们猜想红景 I 号方是通过调控JNK/SAPKs信号通路，从而抑制CCSMC表型转化，本课题的研究结果与假设有一定出入，今后尚需更严密的实验进行论证。本实验结果为ED的临床治疗提供新策略，同时为开发和研究治疗ED的中药提供新思路。